ArticleBiophysical journal2019
Influence of Transmembrane Helix Mutations on Cytochrome P450-Membrane Interactions and Function.
Article in Biophysical journal, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 43 citations in OpenAlex.
- Mechanistic and spectroscopic characterization of human CYP17A1 in Nanodiscs.Journal of inorganic biochemistry · 2026Review
- Natural Polymorphic Variants in the CYP450 Superfamily: A Review of Potential Structural Mechanisms and Functional Consequences.International journal of molecular sciences · 2025Review
- Thylakoid Targeting Improves Stability of a Cytochrome P450 in the CyanobacteriumACS synthetic biology · 2025Article
- From closed to open: three dynamic states of membrane-bound cytochrome P450 3A4.Journal of computer-aided molecular design · 2025Article
- Bacterial expression, purification, and characterization of human cytochrome P450 3A4 without N-terminal modifications.Archives of biochemistry and biophysics · 2024Article
- Multiresolution molecular dynamics simulations reveal the interplay between conformational variability and functional interactions in membrane-bound cytochrome P450 2B4.Protein science : a publication of the Protein Society · 2024Article
- Charged Amino Acids in the Transmembrane Helix Strongly Affect the Enzyme Activity of Aromatase.International journal of molecular sciences · 2024Article
- Systematic engineering pinpoints a versatile strategy for the expression of functional cytochrome P450 enzymes in Escherichia coli cell factories.Microbial cell factories · 2023Article
- Direct interaction between the transmembrane helices stabilize cytochrome P450 2B4 and cytochrome b5 redox complex.Biophysical chemistry · 2023Article
- A Comprehensive Genome-Wide Investigation of the Cytochrome 71 (Plants (Basel, Switzerland) · 2023Article
- Heterologous Expression of the Hot Pepper ABA 8'-Hydroxylase inJournal of microbiology and biotechnology · 2023Article
- Melatonin Activation by Cytochrome P450 Isozymes: How Does CYP1A2 Compare to CYP1A1?International journal of molecular sciences · 2023Article
- Heterologous Expression of Recombinant Human Cytochrome P450 (CYP) inBiotech (Basel (Switzerland)) · 2023Review
- Non-Ionic Inulin-Based Polymer Nanodiscs Enable Functional Reconstitution of a Redox Complex Composed of Oppositely Charged CYP450 and CPR in a Lipid Bilayer Membrane.Analytical chemistry · 2022Article
- Exploring the Interactome of Cytochrome P450 2E1 in Human Liver Microsomes with Chemical Crosslinking Mass Spectrometry.Biomolecules · 2022Article
- Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Structural and functional analysis of tomato sterol C22 desaturase.BMC plant biology · 2021Article
- Domain-Swap Dimerization ofMolecular pharmacology · 2020Article
- Expression, purification, and functional reconstitution ofBiochimica et biophysica acta. Biomembranes · 2020Article
- The Effect of Force-Field Parameters on Cytochrome P450-Membrane Interactions: Structure and Dynamics.Scientific reports · 2020Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
Human cytochrome P450 (CYP) enzymes play an important role in the metabolism of drugs, steroids, fatty acids, and xenobiotics. Microsomal CYPs are anchored in the endoplasmic reticulum membrane by an N-terminal transmembrane (TM) helix that is connected to the globular catalytic domain by a flexible linker sequence. However, the structural and functional importance of the TM-helix is unclear because it has been shown that CYPs can still associate with the membrane and have enzymatic activity in reconstituted systems after truncation or modification of the N-terminal sequence. Here, we investigated the effect of mutations in the N-terminal TM-helix residues of two human steroidogenic enzymes, CYP 17A1 and CYP 19A1, that are major drug targets for cancer therapy. These mutations were originally introduced to increase the expression of the proteins in Escherichia coli. To investigate the effect of the mutations on protein-membrane interactions and function, we carried out coarse-grained and all-atom molecular dynamics simulations of the CYPs in a phospholipid bilayer. We confirmed the orientations of the globular domain in the membrane observed in the simulations by linear dichroism measurements in a Nanodisc. Whereas the behavior of CYP 19A1 was rather insensitive to truncation of the TM-helix, mutations in the TM-helix of CYP 17A1, especially W2A and E3L, led to a gradual drifting of the TM-helix out of the hydrophobic core of the membrane. This instability of the TM-helix could affect interactions with the allosteric redox partner, cytochrome b5, required for CYP 17A1's lyase activity. Furthermore, the simulations showed that the mutant TM-helix influenced the membrane interactions of the CYP 17A1 globular domain. In some simulations, the mutated TM-helix obstructed the substrate access tunnel from the membrane to the CYP active site, indicating a possible effect on enzyme function.
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